The close correlation between 8-hydroxy-2′-deoxyguanosine and epidermal growth factor receptor activating mutation in non–small cell lung cancer

SummaryPatients with non–small cell lung cancer harboring mutations in the epidermal growth factor receptor gene, including delE746-A750 and L858R, are highly sensitive to therapy with epidermal growth factor receptor–targeting drugs, such as gefitinib and erlotinib, in comparison with those harboring wild-type epidermal growth factor receptor. It remains unclear how such epidermal growth factor receptor mutations are induced. In this study, we examined whether 8-hydroxy-2′-deoxyguanosine, a representative oxygen nucleotide of DNA, could play a role in activating mutations of the epidermal growth factor receptor gene and also whether Y-box binding protein–1 and 8-oxoguanine DNA glycosylase that are involved in repair of oxidative stimuli-induced DNA damages could play any role in epidermal growth factor receptor activating mutations. Immunohistochemistry was used to evaluate the expression of 8-hydroxy-2′-deoxyguanosine, Y-box binding protein–1, and 8-oxoguanine DNA glycosylase in patients with non–small cell lung cancer (N = 170). We analyzed mutations of delE746-A750 and L858R in the epidermal growth factor receptor gene using peptide nucleic acid–locked nucleic acid polymerase chain reaction clamping. In non–small cell lung cancer patients, nuclear 8-hydroxy-2′-deoxyguanosine expression was strongly associated with these epidermal growth factor receptor mutations. Furthermore, nuclear expression of Y-box binding protein–1 was inversely associated with epidermal growth factor receptor mutations; but nuclear expression of 8-oxoguanine DNA glycosylase was not. Among 51 patients who were treated with gefitinib, progression-free survival was substantially better when 8-hydroxy-2′-deoxyguanosine expression was positive, when epidermal growth factor receptor mutations were present, and when nuclear Y-box binding protein–1 expression was negative. Thus, activating mutations of the epidermal growth factor receptor gene in non–small cell lung cancer were closely associated with a decrease in the damage repair process for 8-hydroxy-2′-deoxyguanosine in oxidized DNA.